rs2069422

Variant names:

• chr9-22008027-G-T
• rs2069422
• NM_004936.4:c.156+771C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004936.4(CDKN2B):​c.156+771C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 152,216 control chromosomes in the GnomAD database, including 62,721 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.91 (62721 hom., cov: 32)
• Consequence: CDKN2B NM_004936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493
• Publications: 23 publications found

Genes affected

CDKN2B (HGNC:1788): (cyclin dependent kinase inhibitor 2B) This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2B	NM_004936.4	c.156+771C>A		intron_variant	Intron 1 of 1	ENST00000276925.7	NP_004927.2
CDKN2B-AS1	NR_003529.4	n.371+12866G>T		intron_variant	Intron 1 of 18	ENST00000428597.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2B	ENST00000276925.7	c.156+771C>A		intron_variant	Intron 1 of 1	1	NM_004936.4	ENSP00000276925.6
CDKN2B-AS1	ENST00000428597.7	n.371+12866G>T		intron_variant	Intron 1 of 18	1	NR_003529.4

Frequencies

GnomAD3 genomes AF: 0.908 AC: 138078 AN: 152098 Hom.: 62682 Cov.: 32

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.953

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.907

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.908 AC: 138174 AN: 152216 Hom.: 62721 Cov.: 32 AF XY: 0.909 AC XY: 67693 AN XY: 74434

African (AFR) AF: 0.902 AC: 37456 AN: 41524

American (AMR) AF: 0.922 AC: 14092 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3082 AN: 3468

East Asian (EAS) AF: 0.980 AC: 5087 AN: 5190

South Asian (SAS) AF: 0.951 AC: 4591 AN: 4830

European-Finnish (FIN) AF: 0.916 AC: 9698 AN: 10590

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.899 AC: 61124 AN: 68002

Other (OTH) AF: 0.908 AC: 1920 AN: 2114

Alfa AF: 0.904 Hom.: 41668

Bravo AF: 0.909

Asia WGS AF: 0.955 AC: 3302 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.39
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2069422; hg19: chr9-22008026;